The present invention relates to an integral, multi-step commercial process for the production of intravenously administrable immune serum globulin containing IgG (.gamma.-globulin) as the main ingredient.
Various processes are known for obtaining intravenously administrable .gamma.-globulin solutions from starting materials resulting from Cohn fractionation of human plasma. Certain of the Cohn fractions contain higher titres of .gamma.-globulin than others. Usual starting materials for a .gamma.-globulin solution are Cohn Fraction II or Cohn Fraction II+III.
Although prior art processors employ various separation and sterilization techniques, process modifications are constantly sought for improving final product purity and safety, and overall yield.
Many commercial processes employ either a solvent/detergent step for viral inactivation, or a heat treatment step for viral inactivation. To date, the art has not provided a multi-step process beginning with Cohn Fraction II paste or II+III paste including two different viral inactivation procedures as part of an efficient, high yield .gamma.-globulin manufacturing process. The manufacturing process can be continuous.
U.S. Pat. No. 5,151,499 by Kameyama et al. is directed to a process for producing viral inactivated protein compositions in which a protein composition is subjected to a viral inactivation for envelope viruses in a solvent/detergent treatment of the protein composition and a viral inactivation for non-envelope viruses in a heat treatment of the protein composition. The '499 patent teaches that preferably the solvent/detergent step occurs first and in the presence of a protease inhibitor, followed by a heat treatment. Where the heat treatment is carried out in the liquid state, the protein is first recovered from the solvent/detergent by adsorption onto an ionic exchange column, prior to any heat treatment. The liquid heat treatment can be carried out in the presence of a sugar, sugar alcohol or amino acid stabilizer. Although the '499 patent lists many starting protein compositions including immunoglobulin, its production examples employ Factor IX, thrombin, fibrinogen and fibronectin. Removal of denatured protein produced in a heat treatment step through fractionation is not considered.
U.S. Pat. No. 5,371,196 by Yuki et al. is directed to purifying secretory immunoglobulin A. A liquid heat treatment or various combinations of liquid heat treatment and solvent treatment inactivation are described. A polyethylene glycol fractionation is employed following each step and always as a final step. This patent does not relate to immune globulin of high .gamma.-globulin titre.
Certain prior art processes for production of intravenously injectable .gamma.-globulin solutions describe the incorporation of a liquid heat treatment carried out in the presence of sorbitol heat stabilizer in a multi-step purification procedure beginning with Cohn Fraction II+III paste. In U.S. Pat. No. 4,845,199 by Hirao et al., Cohn Fraction II+III is subjected to polyethylene glycol (hereinafter "PEG") fractionation (8% w/v PEG followed by 12% w/v PEG), then ion exchange chromatography (DEAE-Sephadex) and removal of human blood group antibody prior to a liquid heat treatment in the presence of sorbitol as a protein stabilizer. On the other hand, Example 1 of U.S. Pat. No. 4,876,088 by Hirao et al. describes the preparation of intravenously injectable .gamma.-globulin solution from Cohn Fraction II+III paste in which the paste is suspended in water, its pH adjusted to 5.5 and centrifuged, with the supernatant then being heat treated for viral inactivation in the presence of 33% w/v of sorbitol, followed by PEG fractionation (6%/12%) which would remove heat denatured protein and then by other purification steps including DEAE-Sephadex ion exchange chromatography.